Oral cancer, like other cancers, results from a series of discrete, irreversible and sequential alterations in genes that control cell growth, differentiation and motility. The occurrence of additional genetic aberrations promotes invasion and metastasis. Each year approximately 9,000 deaths are attributed to oral cancer and more than 90% of these are squamous cell carcinomas. The prognosis for patients with oral malignancies continues to be poor with only approximately 50% survival at five years. Unlike many anatomic sites, the oral cavity is readily accessible for physical examination by health care personnel, a fact that should facilitate the early identification of pre-malignant lesions as well as the early diagnosis and less radical treatment of tumors. However, most lesions are not detected until they are advanced or have metastasized. At these stages the effectiveness of chemotherapy, radiotherapy and surgery or combinations of these modalities has been disappointing. Moreover, successful therapy of oral cancer has been significantly hindered by the subsequent development of second primary tumors, a major determinant for treatment failure and death. The goal of our program is scientific excellence in addressing the ravaging problem of oral cancer. We aim to elucidate fully, the genetic changes that contribute to the evolution of oral neoplasia, and to use this knowledge to develop molecular markers of disease progression and novel therapeutic approaches for oral malignancies. Current efforts include the development of new animal models for squamous carcinogenesis, the evaluation of novel therapeutic approaches for cancers of the head and neck, and the analysis of genes expressed in squamous cell carcinomas as part of the recently established Head and Neck Cancer Genome Anatomy Project.